Traditional chemotherapies often suffer from high systemic toxicity and a narrow therapeutic window. To improve the pharmacokinetics (PK) and toxicity profiles of anticancer drugs, various avenues are being pursued, such as nano-sized delivery platforms, receptor-targeted conjugates, and prodrug designs. The rationale behind the latter approach is to generate a precursor molecule, which is converted post administration to the actual bioactive form of the drug enzymatically or in response to a chemical stimulus. Bioactivation may occur during absorption, circulation, or at the tumor site. The benefits of lipophilic prodrugs include efficient retention in, and absorption from, circulation, as well as improved penetration of membranes and accumulation in target tissues.
DNA-targeted platinum-acridine hybrid agents have shown exquisite potency in several solid tumor models. Particularly, non-small cell lung cancer (NSCLC) cells prove to be extremely sensitive to this pharmacophore. Unlike cisplatin and its analogues, platinum-acridines derived from PTACRAMTU (1) do not cross-link DNA bases but produce structurally unique hybrid adducts that are an intrinsically more severe form of DNA damage than the former bifunctional adducts. However, despite their promising cell kill in chemoresistant, intractable cancers, many of the currently existing platinum-acridine compounds show unfavorable ADME (absorption, distribution, metabolism, and excretion) properties, which slow their preclinical development.
The prototype compound 1′, for instance, while inhibiting the growth of xenografted NCI-H460 tumors in mice, showed signs of severe toxicity in the test animals, resulting in a low maximum tolerated dose (MTD). Mice necropsied after treatment with 1′ showed high levels of platinum in normal tissues, but insufficient accumulation in tumors, as well as discoloration of the kidneys, a possible sign of hepatotoxicity or nephrotoxicity.
Chart 1. General Structure of First- and Second-Generation Platinum-Acridine Hybrid Agents
Compound 1 (PT-ACRAMTU, Chart 1; ACRAMTU=1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) represents the prototype of a class of DNA-targeted platinum-acridine hybrid agents, which have shown exquisite potency in several solid tumor models. Non-small cell lung cancer (NSCLC) cells prove to be particularly sensitive to this pharmacophore, with the newer derivatives showing IC50 values in NSCLC cell lines in the low-nanomolar range and activity in tumor xenografts. Using a classical structure-activity relationship (SAR) approach and modular library screening, the chemical stability could be tuned and the off-target reactivity of the pharmacophore could be reduced. Some desired improvements were achieved by modifying the ligand and donor sets around the electrophilic metal. These efforts have led to the development of a derivative (1′″, Chart 1) that shows higher potency than cisplatin by three orders of magnitude (the IC50 values for 1′″ in NCI-H460 and A549 lung cancer cells were 1.3 and 3.9 nM, respectively).
The promising cell kill results in chemoresistant, intractable cancers, platinum-acridines yet the unfavorable ADME (absorption, distribution, metabolism, and excretion) properties, has made the development of modified compounds imperative. The compounds, which currently exist, such as compound 1′, for instance, while inhibiting the growth of xenografted NCI-H460 tumors in mice, showed signs of severe toxicity in test animals, resulting in a low maximum tolerated dose (MTD). Mice necropsied after treatment with compound 1′ showed high levels of platinum in normal tissues, but insufficient accumulation in tumors, as well as discoloration of the kidneys, a possible sign of hepatotoxicity or nephrotoxicity. It is with these drawbacks in mind that the present invention was developed.